Abnormal accumulation, assembly and deposition of the amyloid ss-protein (Ass) is a prominent pathological feature of patients with Alzheimer's disease (AD) and related disorders. Ass peptides are derived through sequential proteolytic processing of the Ass precursor protein (AssPP) by ss- and - secretase activities. AssPP is highly expressed in brain although its physiological functions remain poorly understood. Many functional domains have been identified on secreted forms of AssPP proteins that could participate in variety of neuroprotective activities ranging from proteinase inhibition to ligand binding to cytoprotection. For example, during the previous funding period we unequivocally demonstrated that the Kunitz proteinase inhibitory (KPI) activity of sAssPP limits the extent of cerebral thrombosis. Additional protective activities are likely associated with other biologically active domains present on sAssPP proteins in response to cerebral injuries including chronic neurodegenerative disorders such as AD. The abnormal accumulation and deposition of cerebral Ass peptides can occur from increased production but in most cases is likely due to decreased clearance mechanisms in the CNS. Clearance mechanisms involve factors that can promote Ass efflux from the CNS, mediate Ass degradation, and/or inhibit Ass assembly and deposition. Although numerous molecules have been identified that can influence Ass assembly and deposition in vitro our present understanding of these processes in brain remains incomplete. In this regard, the N-terminal region of AssPP (AssPP18-119) is a highly structured region of the protein that binds to Ass peptides and can inhibit their assembly. Thus, the overall hypothesis that forms the basis of this exploratory R21 proposal is that the N-terminal region of secreted AssPP proteins contributes to the regulation of Ass levels, amyloid formation and deposition in brain through its Ass assembly inhibiting activities. In the present proposal we plan to implement studies to investigate how the N-terminal region of AssPP interacts with Ass peptides in vivo to regulate their assembly, deposition and the pathological consequences associated with these processes. For these studies we will utilize two distinct and well- characterized transgenic mouse models of human Ass deposition coupled with approaches to increase AssPP N-terminal fragment levels in them, to understand how this region of sAssPP might alter pathological outcomes. Finally, this newly identified activity of sAssPP, and in particular the N-terminal AssPP18-119 fragment, may lead to new approaches for developing therapeutic agents to combat pathological Ass accumulation, assembly and deposition that occurs in AD and related amyloid depositing diseases.